Mutations in glucocerebrosidase (GBA) are among the most common identifiable genetic risk factors for Parkinson disease (PD), with a frequency >3% in PD patients who are not Ashkenazi Jewish (AJ) and >15% in AJ PD patients. However, much is unknown about the association between GBA and PD, including the age- specific risk of PD in GBA carriers and the mechanism that mediates this risk. The purpose of this grant is to extend the work of my KL2 and Brookdale Fellowship to estimate PD risk in GBA heterozygotes (Aim 1); identify GBA mutation carriers who may be at higher risk for motor-PD through exploration of non-motor signs of PD (Aim 2); investigate whether this risk of PD in GBA carriers is mediated by low beta-glucocerebrosidase (GCase) enzymatic activity (Aim 3); and, lastly, assess whether the GCase pathway is important in the pathogenesis of idiopathic PD by comparing GCase activity in GBA non-carriers with and without PD (Aim 4). To estimate the risk of PD in GBA carriers (Aim 1), I will continue to obtain family history of PD in parents of gaucher patients at two of the largest Gaucher Centers in the world (Mount Sinai School of Medicine [MSSM], NY, and Shaare Zedek, Jerusalem, Israel). Individuals with Gaucher disease have two GBA mutations; therefore their parents are obligatory carriers of a single GBA mutation. I have already collected information on 237 parents and aim to expand our work to >1000 parents. For Aim 2, 30 parents (of probands recruited at MSSM in Aim 1) will be evaluated for non-motor signs and symptoms of PD, including impairment in cognition, olfaction, color discrimination, rapid-eye-movement sleep behavior disorder (RBD) and autonomic dysfunction and compared to 30 controls (spouses and caregiver controls). We hypothesize that GBA mutation carriers are more likely to demonstrate these signs and symptoms compared to age and gender matched controls from the Center of Parkinson's Disease (CPD) at Columbia University. To explore Aim 3 - whether low GCase activity is associated with increased risk for PD among GBA mutation carriers - we will compare GCase activity in GBA mutation carriers with and without PD using dried blood spot (DBS) assays. We previously tested GCase activity using DBS in 299 participants, including 205 PD and 94 controls. We have identified 24 heterozygote carriers (22 PD, 2 spouses). In Aim 4, we will continue recruiting PD participants and controls to achieve 200 members per group, all without GBA mutations. We will compare GCase activity between these groups to determine if PD cases have lower activity. The K02 will allow me to obtain additional training in genetic epidemiology and acquire experience in conducting large multi-site studies. I am currently the recipient of two mentored grants, a KL2 through Columbia's CTSA and the Brookdale Foundation Leadership in Aging Fellowship. Supported by an outstanding group of researchers and collaborators, this grant will provide an excellent foundation for my independent research career. PUBLIC HEALTH RELEVANCE: Mutations in glucocerebrosidase are present in more than 15% of Ashkenazi Jews with Parkinson disease, and 3% of non-Ashkenazi patients with Parkinson disease. This study will provide information on the link between the mutations and Parkinson, including the magnitude of the risk of PD in mutation carriers and the mechanisms mediating this risk.